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Publication numberUS4568743 A
Publication typeGrant
Application numberUS 06/393,646
Publication dateFeb 4, 1986
Filing dateJun 29, 1982
Priority dateOct 21, 1980
Fee statusLapsed
Also published asCA1198732A1, DE3141586A1, DE3141586C2, US4465688, US4826996
Publication number06393646, 393646, US 4568743 A, US 4568743A, US-A-4568743, US4568743 A, US4568743A
InventorsBraham Shroot, Jean Maignan, Gerard Lang
Original AssigneeGroupement D'interet Economique Dit Centre International De Recherches Dermatolgiques C.I.R.D.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
1,8,-Dihydroxy-9-anthrones substituted in the 10-position
US 4568743 A
Abstract
The invention concerns 1,8-dihydroxy-9-anthrones substituted in the 10-position of the formula: ##STR1## in which: R1 represents a group taken from the set constituted by: wherein R2 represents H, C1-8 alkyl, C1-3 mono- or poly-hydroxyalkyl, carbamoly or phenyl,
R3, R4, and R5 represent H, C1-8 alkyl, C3-8 mono- or poly-hydroxyalkyl, possibly interrupted by an oxygen, C3-6 cycloalkyl, or R3 and R4 form a divalent group: --(CH2).sub.(4 or 5) --, --(CH2)2 --O--(CH2)2 --, or --(CH2)2 --N(R8)--(CH2)2 --, R8 being H, --CH3, or --CH2 CH2 OH,
R6 represents 13 CO2 R5, --CN, --CHO, --CONH2, or --CONH--CH2 OH,
and R7 and R'7 are H or --CH3, and their optical isomers.
Utilization of the compounds (I) in human or veterinary medicine, in particular in the treatment of psoriasis and of warts, and in cosmetics.
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Claims(5)
We claim:
1. A compound of the formula: ##STR16## wherein R1 is ##STR17## R3, R4 and R5 are independently selected from the group consisting of hydrogen, alkyl radical having 1-8 carbon atoms, mono- or poly-hydroxyalkyl radical having 3-8 carbon atoms, the carbon chain of which may also contain at least one oxygen atom and cycloalkyl radical having 3-6 carbon atoms, or R3 and R4 together form a divalent group selected from the group consisting of ##STR18## n being 4 or 5, and R8 being selected from the group consisting of hydrogen, methyl and 2-hydroxyethyl.
2. The compound of claim 1 in the form of an optical isomer thereof.
3. The compound of claim 1 wherein the alkyl radical having 1-8 carbon atoms is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hexyl and octyl.
4. The compound of claim 1 wherein the cycloalkyl radical having 3-6 carbon atoms is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
5. A compound of the formula ##STR19## wherein R3 and R4 are independently selected from the group consisting of hydrogen, alkyl radical having 1-8 carbon atoms, mono- or poly-hydroxyalkyl radical having 3-8 carbon atoms, the carbon chain of which may also contain at least one oxygen atom and cycloalkyl radical having 3-6 carbon atoms, or R3 and R4 together form a divalent group selected from the group consisting of: ##STR20## n being 4 or 5, and R8 being selected from the group consisting of hydrogen, methyl and 2-hydroxyethyl.
Description

This application is a continuation-in-part of U.S. patent application Ser. No. 312,671, filed Oct. 19, 1981 and now abandoned.

The present invention has as its object new chemical compounds belonging to 1,8-dihydroxy-9-anthrones substituted in the 10-position, as well as their use in human and veterinary medicine, in particular in the treatment of psoriasis and of warts, and in cosmetics.

The 1,8-dihydroxy-9-anthrones substituted in the 10-position can be represented by the following general formula: ##STR2## in which: R1 represents a group taken from the set constituted by: ##STR3## R2 representing a hydrogen atom, a straight or branched chain alkyl group having 1-8 carbon atoms, a mono- or poly-hydroxyalkyl group, straight or branched chain, and having 1-3 carbon atoms, a carbamoyl group, or a phenyl group,

R3, R4, and R5 representing a hydrogen atom, an alkyl group having 1-8 carbon atoms, a mono- or poly-hydroxyalkyl group, which may be interrupted by an oxygen atom and has 3-8 carbon atoms, or a cycloalkyl group having 3-6 carbon atoms,

or R3 and R4, taken together, form a divalent group taken from the set constituted by: ##STR4## R8 being a hydrogen atom, a methyl group, or a 2-hydroxyethyl group, R6 representing --CO2 R5, --CN, --CHO, --CONH2, or --CONH--CH2 OH,

and R7 and R'7 representing a hydrogen atom or a methyl group, and the optical isomers.

The compounds according to the invention can likewise exist in the form of salts when the group R1 represents the group (b) and/or the group (c) in which R5 represents a hydrogen atom.

In that case these salts correspond to the following general formulas: ##STR5## in which: R3 and R4 have the same meanings as given above for formula (I).

Among the straight or branched chain alkyl groups with 1-8 carbon atoms as denoted in the groups R2, R3, R4, and R5, the following groups can in particular be cited: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, hexyl, and octyl.

Among the straight or branched chain mono- or polyhydroxyalkyl groups, having 1-3 carbon atoms, the following can in particular be cited: hydroxymethyl, 2-hydroxymethyl, 2-hydroxypropyl, and 1,2-dihydroxypropyl.

Among the cycloalkyl groups as denoted by the group R3 or R4, the following groups can in particular be cited: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

By "lower alkyl group" according to the invention there is meant straight or branched chain groups having 1-4 carbon atoms such as methyl, ethyl, propyl, etc.

Among the compounds of formula I in which the group R1 represents the group (a), there can be cited in particular those collected below in Table I.

              TABLE I______________________________________ ##STR6##Com-poundNo.                      R2______________________________________1     10-(1,8-dihydroxy-9-anthrone)-                    H yl succinimide2     10-(1,8-dihydroxy-9-anthrone)-                    CH3 yl Nmethyl succinimide3     10-(1,8-dihydroxy-9-anthrone)-                    CH2 OH yl Nhydroxymethyl succinimide4     10-(1,8-dihydroxy-9-anthrone)-                    CH2 CH2 OH yl N(2-hydroxyethyl succinimide)5     10-(1,8-dihydroxy-9-anthrone)-                    CH2 CH3 yl Nethyl succinimide6     10-(1,8-dihydroxy-9-anthrone)-                    CH2 CHOHCH2 OH yl N(2,3-dihydroxypropyl) succinimide7     10-(1,8-dihydroxy-9-anthrone)-                    CH2 CHOHCH3 yl N(2-hydroxypropyl) succinimide8     10-(1,8-dihydroxy-9-anthrone)-                    CONH2 yl Ncarbamoyl succinimide9     10-(1,8-dihydroxy-9-anthrone)-                    C6 H5 yl Nphenyl succinimide______________________________________

Among the compounds of formula I in which the group R1 represents the group (c), there can be cited in particular those collected below in Table II.

                                  TABLE II__________________________________________________________________________ ##STR7##                           (e)CompoundNo.                    R7                      R'7                          R6__________________________________________________________________________10    Ethyl 3-[10-(1,8-dihydroxy-9-                  H   H   CO2 C2 H5 anthrone)-yl]-propanoate11    3-[10-(1,8-dihydroxy-9-anthrone)-yl]-                  H   H   CO2 H propanoic acid12    3-[10-(1,8-dihydroxy-9-anthrone)-yl]-                  H   H   CHO propanal13    3-[10-(1,8-dihydroxy-9-anthrone)-yl]-                  H   H   CN propionitrile14    3-[10-(1,8-dihydroxy-9-anthrone)-yl]-                  H   H   CONH2 propionamide15    Methyl 3-[10-(1,8-dihydroxy-9-                  CH3                      H   CO2 CH3 anthrone)-yl] butanoate16    Methyl 3-[10-(1,8-dihydroxy-9-                  H   CH3                          CO2 CH3 anthrone)-yl]-2-methyl-propionate17    3-[10-(1,8-dihydroxy-9-anthrone)-yl]                  CH3                      H   CO2 H butanoic acid18    3-[10-(1,8-dihydroxy-9-anthrone)-yl]-                  H   CH3                          CO2 H 2-methylpropionic acid__________________________________________________________________________

Among the compounds of formula I in which the group R1 represents the group (b) and/or (c), there can be cited in particular those collected below in Table III.

                                  TABLE III__________________________________________________________________________ ##STR8##CompoundNo.                      R3      R4      R5__________________________________________________________________________19    10-(1,8-dihydroxy-9-anthrone)-yl                    H            H            H succinamic acid20    10-(1,8-dihydroxy-9-anthrone)-yl                    H            CH3     H Nmethyl succinamic acid21    10-(1,8-dihydroxy-9-anthrone)-yl                    H            C2 H5                                              H Nethyl succinamic acid22    10-(1,8-dihydroxy-9-anthrone)-yl                    H            n-C3 H7                                              H Npropyl succinamic acid23    10-(1,8-dihydroxy-9-anthrone)-yl                    H            iso-C3 H7                                              H Nisopropyl succinamic acid24    10-(1,8-dihydroxy-9-anthrone)-yl                    H            n-C4 H9                                              H Nbutyl succinamic acid25    10-(1,8-dihydroxy-9-anthrone)-yl                    H            cyclohexyl   H Ncyclohexylsuccinamic acid26    10-(1,8-dihydroxy-9-anthrone)-yl                    H            C8 H17                                              H Noctylsuccinamic acid27    10-(1,8-dihydroxy-9-anthrone)-yl                    H            CH2CH 2 OH                                              H N(2-hydroxyethyl)-succinamic acid28    10-(1,8-dihydroxy-9-anthrone)-yl                    H            CH2CHOHCH 2 OH                                              H N(2,3-dihydroxypropyl)-succinamic acid29    10-(1,8-dihydroxy-9-anthrone)-yl                    (CH2)2O(CH2)2                                              H morpholinosuccinamic acid30    10-(1,8-dihydroxy-9-anthrone)-yl                    (CH2)4          H pyrrolidinosuccinamic acid31    10-(1,8-dihydroxy-9-anthrone)-yl                    (CH2)5          H piperidino-succinamic acid32    10-(1,8-dihydroxy-9-anthrone)-yl dimethylsuccinamic                     ##STR9##                 H33    10-(1,8-dihydroxy-9-anthrone)-yl 4-hydroxyethylpiperazino- succinami c acid                     ##STR10##34    10-(1,8-dihydroxy-9-anthrone)-yl                    CH3     CH3     H N,Ndimethylsuccinamic acid35    10-(1,8-dihydroxy-9-anthrone)-yl                    C2 H5                                 C2 H5                                              H N,Ndiethylsuccinamic acid36    10-(1,8-dihydroxy-9-anthrone)-yl                    nC3 H7                                 nC3 H7                                              H N,Ndipropylsuccinamic acid37    10-(1,8-dihydroxy-9-anthrone)-yl                    nC4 H9                                 nC4 H9                                              H N,Ndi-n-butylsuccinamic acid38    10-(1,8-dihydroxy-9-anthrone)-yl                    CH2CH 2 OH                                 CH2CH 2 OH                                              H N,Ndi-(2-hydroxyethyl)- succinamic acid39    10-(1,8-dihydroxy-9-anthrone)-yl                    H            (CH2)2O(CH2)2                                 OH           H N(2-hydroxyethyloxyethyl)- succinamic acid40    Methyl 10-(1,8-dihydroxy-9-                    H            H            CH3 anthrone)-yl 3-carbamoylpropanoate41    Methyl 10-(1,8-dihydroxy-9-                    H            CH3     CH3 anthrone)-yl 3-Nmethylcarbamoyl- propanoate42    Methyl 10-(1,8-dihydroxy-9-                    H            C2 H5                                              CH3 anthrone)-yl 3-Nethylcarbamoyl- propanoate43    Methyl 10-(1,8-dihydroxy-9-                    H            C3 H7                                              CH3 anthrone)-yl 3-Npropylcarbamoyl- propanoate44    Methyl 10-(1,8-dihydroxy-9-                    H            C4 H9                                              CH3 anthrone)-yl 3-Nbutylcarbamoyl- propanoate45    Methyl 10-(1,8-dihydroxy-9-                    H            cyclohexyl   CH3 anthrone)-yl 3-Ncyclohexyl- carbamoylpropanoate46    Methyl 10-(1,8-dihydroxy-9-                    CH2 CH2 OH                                 CH2 CH2 OH                                              CH3 anthrone)-yl 3-N,Ndi-(2- hydroxyethyl)-carbamoylpropanoate47    Methyl 10-(1,8-dihydroxy-9-                    H            CH2CH 2 OH                                              CH3 anthrone)-yl 3-N hydroxyethylcarbamoylpropanoate48    Methyl 10-(1,8-dihydroxy-9-                    H            CH2CHOHCH 2 OH                                              CH3 anthrone)-yl 3-(N2,3-di- hydroxypropylcarbamoyl)-propanoate49    Methyl 10-(1,8-dihydroxy-9-                    H            (CH2)2O(CH2)2                                 OH           CH3 anthrone)-yl 3-[N(2-ethyloxy- ethyl)]-carbamoylpropanoate50    Methyl 10-(1,8-dihydroxy-9-                    (CH2)2O(CH2).sub.                                              CH3 anthrone)-yl 3-Nmorpholinocar- bamoylpropanoate51    Methyl 10-(1,8-dihydroxy-9-                    (CH2)4          CH3 anthrone)-yl 3-Npyrrolidinocar- bamoylpropanoate52    Methyl 10-(1,8-dihydroxy-9-                    (CH2)5          CH3 anthrone)-yl 3-Npiperidinocarba- moylpropanoate53    Methyl 10-(1,8-dihydroxy-9-                    CH3     CH3     CH3 anthrone)-yl 3(N,Ndimethylcarba- moyl)-propanoate54    Ethyl 10-(1,8-dihydroxy-9-                    CH2CH 2 OH                                 CH2CH 2 OH                                              C2 H5 anthrone)-yl 3-[N,Ndi(2- hydroxyethyl)-carbamoyl]-propanoate55    Ethyl 10-(1,8-dihydroxy-9-                    H            CH2CH 2 OH                                              C2 H5 anthrone)-yl 3-(Nhydroxyethyl)- carbamoylpropanoate56    Ethyl 10-(1,8-dihydroxy-9-                    CH2CHOHCH 2 OH                                 CH2CHOHCH 2 OH                                              C2 H5 anthrone)-yl 3-N,N(dihydroxypro- pyl)-carbamoylpropanoate57    Ethyl 10-(1,8-dihydroxy-9-                    H            (CH2)2O(CH2)2                                 OH           C2 H5 anthrone)-yl 3-N(2-hydroxyethyl- oxyethyl)-carbamoylpropanoate58    Ethyl 10-(1,8-dihydroxy-9- anthrone)-yl 3-(4-methylpiper- azino)-car bamoylpropanoate                     ##STR11##                C2 H559    Ethyl 10-(1,8-dihydroxy-9- anthrone)-yl 3-(4-hydroxyethylpi- perazino)-carbamoylpropanoate                     ##STR12##                C2 H5__________________________________________________________________________

Among the primary or secondary amine salts of formula IIb or IIc, there can be cited in particular the compounds collected below in Table IV:

                                  TABLE IV__________________________________________________________________________CompoundNo.                         R3  R4__________________________________________________________________________60    Ammonium 10-(1,8-dihydroxy-9-anthrone)-yl                       H        H 3-carbamoylpropanoate61    Methylammonium 10-(1,8-dihydroxy-9-                       H        --CH3 anthrone)-yl 3-carbamoylpropanoate62    Ethylammonium 10-(1,8-dihydroxy-9-                       H        --C2 H5 anthrone)-yl 3-carbamoylpropanoate63    Propylammonium 10-(1,8-dihydroxy-9-                       HnC3 H7 anthrone)-yl 3-carbamoylpropanoate64    2-hydroxyethylammonium 10-(1,8-dihydroxy-9-                       H        --CH2 --CH2 OH anthrone)-yl 3-N--(2-hydroxyethyl)- carbamoylpropanoate65    di-(2-hydroxyethylammonium) 10-(1,8-                       --CH2 --CH2 OH                                --CH2 --CH2 OH dihydroxy-9-anthrone)-yl 3-N,N-- di-(2- hydroxyethyl)-carbamoylpropanoate66    2,3-dihydroxypropylammonium 10-(1,8-                       H        --CH2 --CHOH--CH2 OH dihydroxy-9-anthrone)-yl 3-N--(2,3- dihydroxypropyl)-carbamoylpropanoate67    2-hydroxyethyloxyethylammonium 10-(1,8-                       H        --(CH2)2 --O--(CH2).su                                b.2 OH dihydroxy-9-anthrone)-yl 3-N--(2- hydroxyethyloxyethyl)-carbamoylpropanoate68    Morpholinium 10-(1,8-dihydroxy-9-                       --(CH2)2 --O--(CH2)2 anthrone)-yl-3-morpholino-propanoate69    Pyrrolidinium 10-(1,8-dihyrroxy-9-                       --(CH2)4 -- anthrone)-yl-3-(pyrrolidinocarbamoyl)- propanoate__________________________________________________________________________

Among the compounds of formula I in which the group R1 represents the group (d), there can be cited in particular those collected below in Table V.

              TABLE V______________________________________ ##STR13##Com-poundNo.                       R3  R4______________________________________70    10-(1,8-dihydroxy-9-anthrone)-yl                     H        CH3 N,N'dimethyl-disuccinamide71    10-(1,8-dihydroxy-9-anthrone)-yl                     H        C2 H5 N,N'diethyl-disuccinamide72    10-(1,8-dihydroxy-9-anthrone)-yl                     H        iso-C3 H7 N,N'diisopropyl-disuccinamide73    10-(1,8-dihydroxy-9-anthrone)-yl                     H        nC4 H9 N,N'dibutyl-disuccinamide74    10-(1,8-dihydroxy-9-anthrone)-yl                     CH3 CH3 N,N'tetramethyl-disuccinamide75    10-(1,8-dihydroxy-9-anthrone)-yl                     C2 H5                              C2 H5 N,N'tetraethyl-disuccinamide______________________________________

The compounds according to the invention are prepared by the Michael reaction according to the method described by O. E. Schultz and G. Frey, Arch. Pharm. 310, 781-787 (1977), consisting of reacting 1,8-dihydroxy-9-anthrone (or anthralin) in an organic solvent under an inert atmosphere, possibly in the presence of a basic catalyst, with an unsaturated compound in which the double bond is conjugated and activated by an electronegative unsaturated group.

The reaction is, in general, carried out at the boiling temperature of the organic solvent for at least 8 hours, and 4-dimethylaminopyridine or lithium or sodium methylate are preferably utilized as basic catalyst.

When the product crystallizes within the reaction mixture when formed or on cooling, it is filtered off, washed, then dried under reduced pressure.

In the other cases, the reaction medium is concentrated under reduced pressure, and the residue is either crystallized from an appropriate solvent or purified by chromatography on silica gel.

The synthesis of the compounds according to the invention can be represented by the following reaction scheme (A): ##STR14##

The compounds of formula (3) are obtained by reacting a molar equivalent of maleimide R2 =H or an N-substituted maleimide (2) R2 ≠H with anthralin (1).

The compounds of formula (5b or 5c) are obtained by reacting maleamic acid (4) X=OH and Y=--NH2, or an N-substituted derivative of maleamic acid (4) X=OH and Y=NR3 R4 with R3 =H and R4 ≠H, or a N,N-disubstituted derivative of maleamic acid (4) X=OH and Y=NR3 R4 with R3 =R4 ≠H with anthralin (1).

The compounds of formula (7) are obtained by reacting an unsaturated compound of formula (6), preferably in excess, with anthralin (1).

Finally, the compounds of formula (9) are obtained by reacting a dimealamide (8) with anthralin (1).

The compounds of formula (5b) or (5c) can likewise be obtained according to another method, as in the following reaction scheme (B): ##STR15##

This process consists of first preparing the 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride of formula (11) according to the procedure described by O. E. Schultz and G. Frey (Arch. Pharm. 310, 776-780 (1977)) by a Michael reaction between anthralin (1) on the one hand and maleic anhydride (10) on the other.

It is possible to obtain from the intermediate compound (11) compounds of formula (5b) or (5c) by reacting it with a molar equivalent of primary or secondary amine at a temperature comprised between -10 and 50 C.

The salts of formula (IIb) and (IIc) can also be obtained starting with the intermediate compounds (11) by reacting under the same conditions two equivalents of the corresponding primary amine or secondary amine with the anhydride.

The salts of formula (IIb) and (IIc) can furthermore be obtained from compounds of formula (5b) or (5c) by washing with hydrochloric acid.

The compounds of formula (5) obtained by a Michael reaction according to reaction scheme (A) or reaction scheme (B) can exist in the form of a mixture of isomers, i.e., of compounds of formula 5b and 5c, to the degree that the reaction cannot always be directed with certainty.

Finally, it must be remarked that the compounds according to the invention, with the exception of the compounds in which R7 =R'7 =H, all possess at least one asymmetric carbon atom, such that they can likewise exist in the form of their optical isomers (d and 1) or of a mixture of these isomers.

The unsaturated starting compounds for the preparation of the compounds according to the invention are mainly commercially available or can be obtained by known methods which are described in the literature. Thus, N-hydroxymethyl-maleimide can be prepared by the action of formaldehyde on maleimide according to the method described by: P. O. Tawney, et al., JOC, p. 15 (1961).

N-carbamoylmaleimide can be prepared according to the method described by P. O. Tawney, et al., JOC, Vol. 25, p. 56 (1960); the dimaleimides are prepared according to the method described by M. Roth, Helv. Chim. Act. 62, p. 1966 (1979).

The N-substituted maleamic acids are likewise prepared by opening of maleic anhydride by a primary or secondary amine, according to the method described by Y. Liwschitz, et al., JACS, 78, 3069 (1956).

The object of the present invention is likewise the utilization of the compounds according to the invention in human or veterinary medicine, in particular in the treatment of psoriasis and/or warts, and in cosmetics.

Cutaneous psoriasis is essentially manifested by the appearance of dry, whitish, or nacreous scales.

Psoriasis preferentially manifests on the knees and elbows, on the sacrum, on the soles of the feet, the palms of the hands, the face, and likewise on hairy hide.

The trials carried out enabled showing that these compounds have good activity when incorporated in various pharmaceutical vehicles intended for utilization by the systemic route and, in particular, percutaneously.

Several examples of preparation of the compounds according to the present invention will now be given, by way of illustration and without any limitative nature.

EXAMPLE 1 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-succinimide (No. 1)

To an agitated solution of 1.12 g of anthralin (5 mmol) in 40 ml of chloroform, there are added, in one addition, 0.48 g of maleimide (1 eq.) and also several crystals of 4-dimethylamino pyridine, with protection from light and under an inert atmosphere.

The reaction mixture is then kept at the boiling point of chloroform for about 7 hours. A yellow solid crystallizes during the reaction. After the end of the reaction, followed by thin layer silica gel chromatography, the reaction medium is left to return to ambient temperature.

The solid is then filtered off, dried under reduced pressure, and gives 1.3 g of 10-(1,8-dihydroxy-9-anthrone)-yl-succinimide, pale yellow in color, having a decomposition point of 220 C.

______________________________________Analysis: C18 H13 NO5______________________________________Calc.    C:    66.87   H:  4.05  N:  4.33  O:  24.74Found:         66.85       4.15      4.43      24.65______________________________________
EXAMPLE 2 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-N-hydroxymethyl succinimide (No. 3)

According to the same procedure as described in Example 1 above, 1.12 g of anthralin are reacted in chloroform in the presence of 0.63 g of N-hydroxymethyl maleimide (1 eq.) in the presence of several crystals of DMAP.

After the end of the reaction a yellow solid, decomposing at 200 C., is isolated from the reaction mixture.

______________________________________Analysis: C19 H15 NO6______________________________________Calc.     C:    64.58     H:  4.28   N:  3.96Found:          65.01         4.32       4.00______________________________________
EXAMPLE 3 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-N-ethyl succinimide (No. 5)

Under a nitrogen atmosphere and protected from atmospheric moisture and from light, a solution of 4.5 g of anthralin with 1.1 equivalent of N-ethyl maleimide and 20 mg of 4-dimethylamino-pyridine in 100 ml of chloroform is kept at the boiling point of chloroform for fifteen hours.

The reaction mixture, after cooling, is deposited directly onto a silica gel column. The expected product is eluted with ethyl acetate. After evaporation of the elution phases, there are obtained 6.5 g of bright yellow crystals having a melting point of 200 C.

______________________________________Analysis: C10 H17 NO5______________________________________Calc.    C:    68.37   H:  4.88  N:  3.99  O:  22.77Found:         68.49       4.94      4.03      22.87______________________________________
EXAMPLE 4 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-N-carbamoylsuccinimide (No. 8)

An agitated mixture of 1.1 g of anthralin and one equivalent of N-carbamoyl maleimide in 20 ml of anhydrous acetonitrile, placed under an inert atmosphere and protected from atmospheric moisture and light, is kept at the reflux of acetonitrile for 8 hours.

After cooling, the solid is drained, washed with acetonitrile, then dried under reduced pressure over phosphorus pentoxide. There are thus obtained 1.45 g of yellow crystals having an instantaneous melting point of 200 C.

______________________________________Analysis: C19 H14 N2 O6______________________________________Calc.    C:    62.29   H:  3.85  N:  7.65  O:  26.21Found:         62.17       3.93      7.70      26.22______________________________________
EXAMPLE 5 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-N-phenyl succinimide (No. 9)

An agitated mixture of 4.5 g of anthralin and an equivalent of N-phenyl maleimide in 100 ml of acetonitrile placed under an inert atmosphere and protected from atmospheric moisture and from light is kept at the reflux of acetonitrile for 17 hours. After cooling, the solid is drained, washed with chloroform, then with benzene; after drying at 120 C. under reduced pressure, 7 g of a bright yellow solid are obtained, with an instaneous melting point of 260 C.

______________________________________Analysis: C24 H17 NO5______________________________________Calc.    C:    72.17   H:  4.29  N:  3.51  O:  20.03Found:         72.03       4.25      3.47      20.00______________________________________
EXAMPLE 6 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-propanoic ethyl ester (No. 10)

A mixture of 4.52 g of anthralin (0.02 mol), 6 ml of ethyl acrylate and 1 ml of 0.5% lithium methylate, in 35 ml of anhydrous chloroform is kept at the boiling point of the solvent for 5 hours, protected from light under an inert atmosphere. After the mixture has been left at ambient temperature for about 48 hours, silica gel chromatography is carried out.

The ethyl 10-(1,8-dihydroxy-9-anthrone)-yl propanoate is then eluted with a benzene-chloroform mixture (50/50), then recrystallized from hexane. This compound occurs in the form of a yellow solid with a melting point of 90 C.

______________________________________Analysis: C19 H18 O5______________________________________Calc.     C:    69.93     H:  5.55   O:  24.51Found:          69.83         5.54       24.50______________________________________
EXAMPLE 7 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-propanoic ester (No. 11)

A solution of 6 g of ethyl 10-(1,8-dihydroxy-9-anthrone)-yl propanoate in a mixture of 150 ml of dioxane and 150 ml of 5N hydrochloric acid is kept under an inert atmosphere and protected from light for 2 hours at 100 C.

The reaction mixture is then concentrated under reduced pressure.

The residue is deposted on a silica gel chromatography column and the expected acid is eluted with a 1:1 benzene/ethyl acetate mixture, then recrystallized from toluene. There is obtained 1 g of yellow powder with a melting point of 191 C. The mass spectrum gives the expected parent peak at m/e=298 (C17 H14 O5).

EXAMPLE 8 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl succinamic acid (No. 19)

(a) To a solution of 0.678 g of anthralin (310-3 mol) in 25 ml anhydrous acetonitrile under an inert atmosphere and protected from light and atmospheric moisture, there is added 0.345 g (1 eq.) of maleamic acid, in one portion. The reaction mixture is then kept at the boiling point of the solvent for 6 hours. 10-(1,8-dihydroxy-9-anthrone)-yl succinamic acid crystallizes within the reaction mixture as it forms.

At the end of the reaction, as followed by thin layer chromatography, the mixture is kept at ambient temperature; the pale yellow solid is then filtered off, and is dried under reduced pressure.

There are thus obtained 0.85 g of the expected product, which decomposes at 220 C.

______________________________________Analysis: C18 H15 NO6______________________________________Calc.    C:    63.34   H:  4.43  N:  4.10  O:  28.13Found:         63.46       4.44      4.09      28.12______________________________________

(b) To a solution of 0.972 g (310-3 mol) of 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride (prepared according to O. E. Schultz and G. Frey, Arch. Pharm. 310, 776-780, 1977) in 80 ml of acetonitrile, agitated at 5 C. under an inert atmosphere and protected from light, there is added dropwise a solution of ammonia (1 eq.) diluted with 20 ml of acetonitrile. The 10-(1,8-dihydroxy-9-anthrone)-yl succinamic acid precipitates as it is formed. It is drained, then washed with a solution of hydrochloric acid in ether and then dried under reduced pressure. There is thus obtained 0.9 g of a yellow product which decomposes at 220 C.

EXAMPLE 9 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl N-methyl succinamic acid (No. 20)

An agitated mixture of 4.5 g of anthralin, one equivalent of N-ethyl maleamic acid, and 20 mg of 4-dimethylamino pyridine in 50 ml of chloroform is refluxed for 24 hours under an inert atmosphere and protected from light and atmospheric moisture.

After cooling, the yellow solid formed is drained, washed with chloroform, then with a dilute aqueous acetic acid solution, and is then agitated for a long time in water. The solid is again filtered off, then dried over phosphorus pentoxide under reduced pressure. There is thus obtained 1.5 g of yellow crystals with a melting point (decomposition) of 260 C.

______________________________________Analysis: C19 H17 NO6______________________________________Calc.    C:    64.22   H:  4.82  N:  3.94  O:  27.02Found:         64.07       4.79      3.85      26.93______________________________________
EXAMPLE 10 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl N-ethyl succinamic acid (No. 21)

An agitated mixture of 4.5 g of anthralin with an equivalent of N-ethyl maleamic acid and several crystals of DMAP in 50 ml of chloroform is kept at the boiling point of this solvent under agitation and protected from atmospheric moisture and from light, for 8 hours. The mixture is then allowed to come to ambient temperature. The crystals are then filtered off, and are deposited, in chloroform solution, on a silica gel column.

The expected product, contaminated with an impurity, is eluted with ethyl acetate. After concentration of the elution phases, the mixture is taken up in acetone, and the impurity is eliminated by filtration. After concentration of the filtrate, there is obtained 10-(1,8-dihydroxy-9-anthrone)-yl N-ethyl succinamic acid of yellow color, melting at 190 C.

______________________________________Analysis: C20 H19 NO6______________________________________Calc.:   C:    65.03   H:  5.18  N:  3.79  O:  25.99Found:         65.13       5.12      3.78      25.91______________________________________
EXAMPLE 11 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl N-isopropyl succinamic acid (No. 23)

An agitated mixture of 4.5 g of anthralin, an equivalent of N-isopropyl succinamic acid, and 20 mg of 4-dimethyl-aminopyridine in 50 ml of chloroform is refluxed for 24 hours. The reaction mixture is protected from atmospheric moisture and light. After cooling, the precipitate formed is drained, washed with chloroform and then with dilute acetic acid, and is finally dried at 120 C. at reduced pressure over phosphorus pentoxide. There are obtained 3.2 g of yellow crystals with an instantaneous melting point of 220 C.

______________________________________Analysis: C21 H21 NO6______________________________________Calc.:   C:    65.78   H:  5.52  N:  3.65  O:  25.04Found:         65.77       5.55      3.54      24.86______________________________________
EXAMPLE 12 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl N-(2-hydroxyethyl)succinamic acid (No. 27)

At ambient temperature, under an inert atmosphere and protected from light, a mixture is agitated of 0.486 g (1.5 mmol) of 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride and an equivalent of ethanolamine in 50 ml of anhydrous chloroform.

After agitation for 48 hours, a white powder is filtered off and is then treated with a 0.1N solution of hydrochloric acid at 0 C. The 10-(1,8-dihydroxy-9-anthrone)-yl N-(2-hydroxyethyl)succinamic acid is then drained and dried under reduced pressure.

It is a yellow powder which begins to decompose at 120 C.

______________________________________Analysis: C20 H19 NO7______________________________________Calc.:   C:    62.33   H:  4.97  N:  3.63  O:  29.06Found:         62.45       5.00      3.72      29.04______________________________________
EXAMPLE 13 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl morpholinosuccinamic acid (No. 29)

A suspension of 600 mg of the salt of Example 23 below in 10 ml of 5N hydroxhloric acid is agitated for about half an hour. The solid is filtered off, then rapidly washed with acetone. There are thus obtained 300 mg of yellow powder after drying, with a melting point (instantaneous) of 150 C.

______________________________________Analysis: C22 H21 NO7______________________________________Calc.:   C:    64.23   H:  5.14  N:  3.40  O:  27.22Found:         64.14       5.20      3.34      27.34______________________________________
EXAMPLE 14 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl pyrrolidino succinamic acid (No. 30)

A suspension of 1 g of the salt of Example 24 below is agitated in 10 ml of 5N hydrochloric acid at 0 C. under an inert atmosphere for half an hour. The solid is then drained, rapidly washed with acetone, and then dried. 0.5 g of yellow powder is obtained, with an instantaneous melting point of 215 C.

______________________________________Analysis: C22 H21 NO6______________________________________Calc.:   C:    66.83   H:  5.35  N:  3.54  O:  24.28Found:         66.87       5.34      3.59      24.48______________________________________
EXAMPLE 15 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl 4-methylpiperazino succinamic acid (No. 32)

To a solution of 1.35 g of anthralin (6 mmol) in 180 ml of chloroform placed under an inert atmosphere, there are added, with protection from light, 1.2 g of 4-methylpiperazino maleamic acid. This mixture is agitated and brought to the boiling temperature of the solvent during 18 hours. The expected product crystallizes from the solution as it forms.

After cooling, it is drained, then dried under reduced pressure at 120 C. There are thus obtained 1.32 g of 10-(1,8-dihydroxy-9-anthrone)-yl 4-methylpiperazino succinamic acid, in the form of a pale yellow powder which decomposes at 210 C.

______________________________________Analysis: C23 H24 N2 O6______________________________________Calc.:   C:    65.08   H:  5.70  N:  6.60  O:  22.62Found:         64.35       5.79      6.54      23.09______________________________________
EXAMPLE 16 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl 4-(2-hydroxyethyl)piperazino succinamic acid (No. 33)

To a solution of 0.972 g (3 mmol) of 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride in 50 ml of chloroform agitated at ambient temperature in an inert atmosphere and exclusion of light, one adds in small fractions an equivalent of 4-(2-hydroxyethyl)piperazine (0.390 g=10 mmol). The reaction mixture is then permitted to stand overnight at ambient temperature. The reaction mixture is then collected and dried under reduced pressure at 120 C.

The product is obtained in the form of a yellow-brown solid decomposing at about 190 C.

______________________________________Analysis: C24 H26 N2 O7 (monohydrate)______________________________________Calc.:   C:    61.01   H:  5.97  N:  5.93  O:  27.09Found:         61.41       5.83      6.24      26.69______________________________________
EXAMPLE 17 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl N,N-di(2-hydroxyethyl)-succinamic acid (No. 38)

To a solution of 0.972 g (3 mmol) of 10-(1,8-dihydroxy-9-anthrone)-yl succinamic acid in 60 ml of acetonitrile, agitated at ambient temperature and under a nitrogen atmosphere, there is slowly added, with protection from light, an equivalent of diethanolamine diluted with 20 ml of acetonitrile. The reaction mixture is then left overnight at ambient temperature.

After the insoluble matter has been removed by filtration, the filtrate is concentrated under reduced pressure. After washing with ether, draining and drying under reduced pressure, a product is obtained which decomposes at about 100 C.

______________________________________Analysis: C22 H23 NO8______________________________________Calc.:    C:    59.05     H:  5.63   N:  3.13Found:          59.05         5.47       3.20______________________________________
EXAMPLE 18 Preparation of Methyl 10-(1,8-dihydroxy-9-anthrone)-yl 3-carbamoylpropanoate (No. 40)

To an agitated solution of 1 g of 10-(1,8-dihydroxy-9-anthrone)-yl succinamic acid in 150 ml of methanol, cooled to 0 C., there is added an excess of diazomethane dissolved in ether.

The mixture is kept overnight at ambient temperature. The next day, after 2 ml of acetic acid have been added to destroy the excess of diazomethane, the reaction medium is concentrated at reduced pressure. The residue obtained is dissolved in the minimum of chloroform, then deposited on a silica gel column. The expected ester is eluted with acetone. After concentration of the acetone, a yellow powder is obtained having a melting point of 250 C.

______________________________________Analysis: C19 H17 NO6______________________________________Calc.:   C:    64.22   H:  4.82  N:  3.94  O:  27.01Found:         64.18       4.84      3.84      26.87______________________________________
EXAMPLE 19 Preparation of Methyl 10-(1,8-dihydroxy-9-anthrone)-yl N-morpholine-3-carbamoylpropanoate (No. 50)

A solution of 0.5 g of 10-(1,8-dihydroxy-9-anthrone)-yl morpholinosuccinamic acid in 30 ml of anhydrous methanol, two drops of sulfuric acid, and 1 ml of 2,2-dimethoxypropane is refluxed for 10 hours under an argon atmosphere and protected from atmospheric moisture and light. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure; the residue is directly taken up in the minimum of benzene. The benzene phase is deposited on a silica gel chromatography column. The expected product is eluted with a benzeneacetone (1:1) mixture. After concentration of the elution phases and drying, 0.30 g of yellow powder are obtained, with a melting point of 158 C.

______________________________________Analysis: C23 H23 NO7______________________________________Calc.:   C:    64.93   H:  5.45  N:  3.29  O:  26.32Found:         64.94       5.46      3.28      26.28______________________________________
EXAMPLE 20 Preparation of 2-hydroxyethylammonium 10-(1,8-dihydroxy-9-anthrone)-yl N-(2-hydroxyethyl)-3-carbamoylpropanoate (No. 64)

To a solution of 0.366 g of ethanolamine (6 mmol) in 50 ml of chloroform, agitated at ambient temperature, there are added in small fractions 0.972 g (3 mmol) of 10-(1,8-dihydroxy-9-anthrone)-yl-succinic anhydride. The reaction medium, after being homogenized, gives rise to crystals of a pale yellow color.

After one night, the crystals are filtered off and dried. The salt thus isolated (1.25 g) is in the form of a pale yellow powder which decomposes at about 170 C.

______________________________________Analysis: C22 H26 N2 O8______________________________________Calc.:   C:    59.18   H:  5.87  N:  6.27  O:  28.67Found:         59.31       5.77      6.20      28.67______________________________________
EXAMPLE 21 Preparation of di(2-hydroxyethyl)ammonium 10-(1,8-dihydroxy-9-anthrone)-yl-N,N-di(2-hydroxyethyl)-3-carbamoylpropanoate (No. 65)

0.972 g of 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride is dissolved in 120 ml of hot, anhydrous acetonitrile. The solution obtained, after filtration, is cooled to 0 C., and there are then added dropwise, with agitation, two equivalents of diethanolamine diluted with 80 ml of acetonitrile.

The expected salt progressively crystallizes; agitation is continued for about 2 hours after the end of addition. After filtering off the solid and drying it under reduced pressure, there are obtained 1.5 g of a product in the form of pale yellow crystals with glints of green, decomposing at about 150 C.

______________________________________Analysis: C26 H34 N2 O10______________________________________Calc.:   C:    58.41   H:  6.41  N:  5.24  O:  29.93Found:         58.52       6.38      5.23      29.92______________________________________
EXAMPLE 22 Preparation of 2-hydroxyethyloxyethyl 10-(1,8-dihydroxy-9-anthrone)-yl N-(2-hydroxyethyloxyethyl)-3-carbamoylpropanoate (No. 67)

Under a nitrogen atmosphere, protected from light, and at ambient temperature, a mixture is agitated of 0.972 g (3 mmol) of 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride and 0.631 g (6 mmol) of 2-hydroxyethyloxyethylamine in 50 ml of chloroform. The medium becomes progressively homogeneous and the amine salt then slowly crystallizes. After one night, the solid is filtered off, then dried under reduced pressure. 1.1 g of product are thus obtained in the form of a beige powder which decomposes at about 150 C.

______________________________________Analysis: C26 H34 N2 O10______________________________________Calc.:   C:    58.41   H:  6.41  N:  5.24  O:  29.93Found:         58.31       6.38      5.28      30.13______________________________________
EXAMPLE 23 Preparation of morpholinium 10-(1,8-dihydroxy-9-anthrone)-yl morpholino-3-carbamoylpropanoate (No. 68)

To an agitated suspension of 1 g of 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride in 100 ml of chloroform, cooled to 0 C. and placed under an inert atmosphere with protection from light, there are added dropwise two equivalents of morpholine. At the end of addition, the solution obtained is filtered. The filtrate is concentrated under reduced pressure.

The solid obtained is dissolved in ether, filtered and then dried under reduced pressure. 1.1 g of beige powder are thus obtained, with an instantaneous melting point of 130 C. This hygroscopic product is analyzed in the from of the hemihydrate.

______________________________________Analysis: C26 H30 N2 O8.1/2H2 O______________________________________Calc.:   C:    61.54   H:  6.11  N:  5.52  O:  26.82Found:         61.79       5.90      4.93      26.98______________________________________
EXAMPLE 24 Preparation of pyrrolidinium 10-(1,8-dihydroxy-9-anthrone)-yl pyrrolidino-3-carbamoylpropanoate (No. 69)

To an agitated suspension of 0 C. of 3.24 g of 10-(1,8-dihydroxy-9-anthrone)-yl succinic anhydride in 150 ml of chloroform, protected from light and from atmospheric moisture under an inert atmosphere, there are slowly added two equivalents of pyrrolidine. After two hours of agitation, the chloroform solution is concentrated under reduced pressure, and the residue is solidified in anhydrous ether. The brown solid thus obtained is filtered off, again washed with ether, then dried under reduced pressure. This brown powder melts at 120 C.; it is very hygroscopic, and is analyzed in the form of the monohydrate.

______________________________________Analysis: C26 H30 N2 O6.1 H2 O______________________________________Calc.:   C:    64.45   H:  6.65  N:  5.78  O:  23.11Found:         63.93       6.70      5.83      23.40______________________________________
EXAMPLE 25 Preparation of 10-(1,8-dihydroxy-9-anthrone)-yl-N,N'-diisopropyl disuccinamide (No. 72)

An agitated mixture of 1 g of anthralin and 1 g of N,N'-diisopropyl dimaleimide in 50 ml of anhydrous acetonitrile is refluxed for 5 hours, protected from atmospheric moisture and from light.

After cooling, the solid is filtered off, washed with acetonitrile, then dried under reduced pressure. There are obtained 1.72 g of pale yellow crystals which decompose at 280 C.

______________________________________Analysis: C24 H28 N2 O5______________________________________Calc.:   C:    67.90   H:  6.65  N:  6.60  O:  18.85Found:         67.87       6.58      6.45      18.68______________________________________

Regarding the treatment of psoriasis or warts, a composition containing a compound of the present invention is topically administered directly to the affected area. It may, for example, be applied as part of a thickened lotion. A suitable thickening agent for such an application would be petroleum jelly.

An example of an anti-psoriasis composition embodied within the scope of the present invention is as follows:

10-(1,8-dihydroxy-9-anthrone)-yl N-carbamoyl succinimide: 1.5 g

Salicyclic acid: 0.7 g

Petroleum jelly: 100 g

To the petroleum jelly at 60 C., it is added under stirring the active ingredient and then the salicylic acid. After cooling to ambient temperatures, the suspension obtained is refined by passing it to a roller mill.

By applying the suspension once a day during three weeks, excellent results are obtained on the psoriasis areas very similar to those obtained with anthraline but with no primary irritation and without staining of the skin.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
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US4327114 *Jan 8, 1981Apr 27, 1982Boehringer Ingelheim GmbhSubstituted 1,8-dihydroxy-9-(10H)anthracenones
Non-Patent Citations
Reference
1 *Meerwein et al., Chem. Abs., vol. 13 (1919), 1310 1313.
2Meerwein et al., Chem. Abs., vol. 13 (1919), 1310-1313.
3 *Schultz et al., Archiv. der Pharmazie, vol. 310 (1977), 776 780.
4Schultz et al., Archiv. der Pharmazie, vol. 310 (1977), 776-780.
Referenced by
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US4826996 *Dec 9, 1985May 2, 1989Groupement D'interet Economique Dit Centre International De Recherches Dermatologioues C.I.R.D.1,8,-dihydroxy-9-anthrones substituted in the 10-position
US4843097 *Apr 4, 1988Jun 27, 1989Groupement D'interet Economique Dit: Centre International De Recherches Dermatologiques C.I.R.D.Antitumor agents, skin disorders, antiinflammatory agents
US4889865 *Feb 21, 1989Dec 26, 1989Centre International De Recherches Dermatologiques C.I.R.D.10-aryl-1,8-dihydroxy-9- anthrones and their esters
US5426197 *Jul 19, 1993Jun 20, 1995Teva Pharmaceutical Industries, Ltd.Antiinflammatory, antiallergy or antitumor agents
US5661187 *Mar 7, 1995Aug 26, 1997Teva Pharmaceutical Industries, Ltd.10-substituted 1,8-dihydroxy-9 (10H) anthracenone pharmaceuticals
US5844004 *Mar 27, 1997Dec 1, 1998Teva Pharmaceutical Industries, Ltd.10-substituted 1,8-dihydroxy-9 (10H) anthracenone pharmaceuticals
US6006031 *Jun 14, 1996Dec 21, 1999Tandem Computers IncorporatedMethod and apparatus for reconciling conflicting translations by factoring and parameterizing differences
US6127426 *Nov 19, 1998Oct 3, 2000Teva Pharmaceutical Industries Ltd.Antiallergic and -inflammatory agents e.g., treating psoriasis, blocked on the c-10 by a nonphenolic arylacyl or a phenylalkylidene group; lipoxygenase inhibitors; antiproliferative agents; low dosage; side effect reduction
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